Drugs are commonly administered in solid form through pills or capsules that can be orally taken. However, many biological drugs can not be administered this way because of degradation in the gastrointestinal tract and quick elimination by the liver. Another common technique for administration of drugs in liquid form is through injection using a metal hypodermic needle that can cause significant pain and discomfort to patients. A number of physical and chemical techniques including electroporation, laser ablation, ultrasound, thermal, iontophoresis and chemical enhancers have been explored to develop painless percutaneous drug delivery techniques. It was found that it is very difficult for molecules with a molecular weight higher than 500 or a diameter larger than 1 nm to penetrate normal human skin.
Further studies showed that the key barrier for percutaneous delivery of substances is the stratum corneum layer, the outer layer of skin, that is about 4-30 micron thick. Invasive methods to overcome this skin barrier have been used in practice, such as intradermal (ID), intramuscular (IM) or subcutaneous (SC) injection using standard hypodermic needles and syringes. These methods cause pain and require a skilled professional. In addition, they may cause needle injuries. Similarly, current methods of extracting biologic fluids such as blood from patients suffer from the same disadvantages.
In order to improve the skin permeability of such therapeutic agents and other active ingredients, microneedles have been recently developed to disrupt the stratum corneum and facilitate the delivery of the active agents and ingredients to the epidermis. These active substances can then diffuse through the rest of the epidermis to the dermis to be absorbed by blood vessels and lymphatics. The substance absorbed can then get into the circulation system. Thus, both topical and systemic delivery of drugs is possible. Since there are no nerves and blood vessels in the stratum corneum and epidermis, this is a minimally invasive, painless and blood-free method of drug delivery. An additional advantage of this method, when engineered for topical delivery of vaccines, can lead to enhanced inoculation effect because the epidermis is rich in antigen presenting cells and is a desired target for vaccine delivery.
The prior art reports many devices and methods to overcome the skin barriers. For example, U.S. Pat. Nos. 5,855,801 and 5,928,207 assigned to The Regents of the University of California taught a microneedle fabrication method similar to IC compatible neural recording arrays. The disclosed microneedle arrays are typically linear arrays as they are in the plane of the silicon substrate surface. Microneedles have also been fabricated by heating the glass tube and lengthening the heated part till the diameter of the tip is reduced to the desired range. However, in general it is very difficult to control the size of the needle shaft and the tip this way, although biologists are still using this method to produce microneedles that can inject or withdraw substances from a single cell.
U.S. Pat. No. 6,503,231 by Prausnitz et al discloses a method for making out-of-the-plane porous or hollow microneedles. It either involves porous silicon formed by anodization of silicon or deals with sacrificial molds or selective removal of substrate materials to form fluidic conduits. U.S. Pat. No. 6,511,463 by JDS Uniphase Corp. also teaches a method to fabricate the same. U.S. Pat. No. 6,558,361 assigned to Nanopass Ltd. teaches a method for the manufacture of hollow microneedle arrays by removing a selective area of substrate material. U.S. Pat. No. 6,603,987 assigned to Bayer Corp. also discloses a method to make a hollow microneedle patch. All these methods are trying to perform certain functions of the current hypodermic needles and create a miniaturized analog to perform drug delivery or extract body fluids without causing pain and discomfort.
More recently, U.S. application publication No. 2004/0199103 describes a single-step method of delivering an active agent using a “solid solution perforator” (“SSP”) which incorporates an active agent in the SSP matrix material itself. The SSP perforates the skin and then the SSP biodegrades and dissolves to release the active agent through the skin. The publication describes that the delivery of the active agent is initiated only after the SSP sufficiently degrades, and delivery is stopped once the SSP is removed from the skin.
U.S. application publication No. 2004/0241965 describes a method of making high aspect ratio electrode arrays comprised of solid metals. It involves the preparation of porous microchannel glass template, electrodeposition of metals in the microchannels, and final preparation of an electrode array following an electrodeposition. The body of microelectrode is formed by electrodeposition method similar to those used in forming nanowires. Microneedles having hollow bodies also require a readily available active agent reservoir or conduit for providing subsequent injection delivery of an active agent.
The prior methods to make microneedles, whether they are in-the-plane or out-of-the-plane from the substrate material, are cumbersome and/or expensive. The hollow microneedle arrays, while their sizes are scaled down from conventional needles, are especially expensive to make and use because of complexity in the fabrication process and the difficulty in providing a readily available active agent reservoir or conduit for injecting an active agent. The mechanical integrity of prior microneedles also suffers as their sizes become smaller and/or as they are made with readily biodegradable materials such as those preferred for use as solid solution perforators. Moreover, incorporating the prior art microneedles and arrays on an applicator device that can be easily used by any individual multiple times, and readily provide an active agent for multiple uses, is likely to be very cumbersome and expensive.
Moreover the FMA microdevice feature described herein has been shown to be effective for enhancing delivery of a variety of active agents, for example, as described in U.S. application publication Nos. 2008/0051695 and 2008/0214987. Also, for example, it has been established that FMA-enhanced delivery of lidocaine effectively manages pain as indicated in U.S. application publication No. 2007/060867, and as reported for a large clinical trial in Li et al., “Microneedle Pretreatment Improves Efficacy of Cutaneous Topical Anesthesia”, Am. J. Emergency Med., 28:130-134 (2010).
Accordingly, there remains a continuing need for an improved low cost, easy to use, multi-use, disposable percutaneous delivery device applicator with active agent for effective through the skin delivery of the active agent in a controlled manner.